Cholesterol

CSIRO is carrying out research in a number of dietary areas to develop strategies for reducing cholesterol levels, the risk of heart disease and other conditions that are food-related and correctable through modification of diet.

High levels of cholesterol are a risk factor for coronary artery disease (heart attacks and angina).

What is it?

Cholesterol is an essential type of fat that is carried in the blood.

All cells in the body need cholesterol for internal and external membranes.

It is also needed to produce some hormones and for other functions.

The body generally makes all the cholesterol it needs.

Some dietary cholesterol is normally excreted via the liver, however eating too much saturated fat leads to excess cholesterol in the blood stream.

Why is high cholesterol a problem?

High levels of cholesterol in the blood stream are a risk factor for coronary artery disease (heart attacks and angina).

If your cholesterol level is 6.5 mmol/L or greater your risk of heart disease is about 4 times greater than that of a person with a cholesterol level of 4 mmol/L.

High blood levels of cholesterol are a risk factor for coronary artery disease (heart attacks and angina).

Not all people with high cholesterol levels get heart disease.

About 30 per cent of the community will die of heart disease and most of these will be over 65 years old.

Heart disease usually takes 60-70 years to develop, but if you discover your cholesterol level is high you should see your doctor within the next 2-3 months, not necessarily tomorrow.

Other risk factors for heart disease include smoking, high blood pressure and obesity.

Cholesterol – the good and the bad

Cholesterol is carried in the blood stream in particles called lipoproteins.

These are named according to how big they are:

the very large particles are called Very Low Density Lipoproteins (VLDL)

the intermediate size ones are called Low Density Lipoprotein (LDL) and these particles cause heart disease

the smallest particles are called High Density Lipoproteins (HDL) and these particles actually protect against heart disease.

What to do if your cholesterol level is high

The most effective way to lower your cholesterol is to reduce the amount of animal fat in your diet by various means.

make cakes at home with polyunsaturated fat, cook chips with polyunsaturated or monounsaturated oil

lose weight if overweight.

If you make a number of changes to your diet you can expect your cholesterol to fall by 10 per cent.

About 15 per cent of people will see no change and another 15 per cent will see changes of 20-30 per cent.

How high is high?

If your cholesterol is between 5.5 and 6.5 your risk of heart disease is only increased by a small amount.

Don’t panic but make a few moderate changes to your diet.

However if you already have heart disease, or one of your parents developed heart disease at an early age, (less than 55 years of age) then you need to make bigger changes.

If your cholesterol is higher than 6.5 then you need to make more changes.

If despite changes to your diet your cholesterol level remains above 6.5 you may need medication, especially if you have the other risk factors mentioned or you have a family history of heart disease- see your doctor.

What about triglycerides?

Triglycerides are a stored energy source.

Most of the triglyceride is found in the very large particles, the VLDL.

Under some circumstances high blood triglyceride can be a risk factor.

If your cholesterol is high (greater than 6.5) and your HDL cholesterol is low (less than 0.9) then triglycerides can increase the risk of heart disease if they are greater than 1.7.

Triglyceride levels greater than 10 can cause inflammation of the pancreas which is a very serious condition.

Cholesterol explained

Cholesterol is a type of fat that is part of all animal cells. It is essential for many of the body’s metabolic processes, including hormone and bile production, and to help the body use vitamin D. However, there’s no need to eat foods high in cholesterol. The body is very good at making its own cholesterol; you don’t need to help it along. In fact, too much cholesterol in your diet can lead to heart disease.

Cholesterol is essential
Cholesterol is produced by the liver and also made by most cells in the body. It is carried around in the blood by little ‘couriers’ called lipoproteins. We need blood cholesterol because the body uses it to:

Build the structure of cell membranes

Make hormones like oestrogen, testosterone and adrenaline

Help your metabolism work efficiently; for example, cholesterol is essential for your body to produce vitamin D

Produce bile acids, which help the body digest fat and absorb important nutrients.

Two types of cholesterol
Cholesterol is a white and waxy substance. There are two types of cholesterol:

Low density lipoprotein (LDL) cholesterol – called the ‘bad’ cholesterol because it goes into the bloodstream and clogs up your arteries.

High density lipoprotein (HDL) cholesterol – called the ‘good’ cholesterol because it helps to take the ‘bad’ cholesterol out of the bloodstream.

Safe blood cholesterol levels
Health authorities recommend that cholesterol levels should be no higher than 5.5mmols per litre. Approximately 50 per cent of adult Australians have a blood cholesterol level above 5mmols per litre. This makes high blood cholesterol a major health concern in Australia.

Effects of high cholesterol levels
The liver is the main processing centre for cholesterol. When we eat animal fats, the liver returns the cholesterol it can’t use to our bloodstream. When there is too much cholesterol circulating in our bloodstream, it can build up into fatty deposits. These deposits cause the arteries to narrow and can eventually block the arteries completely, leading to heart disease and stroke.

You do not need cholesterol in your diet
You don’t need to eat foods that contain cholesterol; your body can produce all the cholesterol it needs. High cholesterol foods are usually foods high in saturated fats. These foods should be limited in a healthy diet.

Foods that contain cholesterol
The cholesterol in your diet comes mainly from the saturated fats found in animal products. All foods from animals contain some cholesterol. Foods from plants do not contain cholesterol. Other sources of dietary cholesterol are full fat dairy foods, eggs and some seafood.

How to avoid saturated fats
The best way to maintain healthy levels of cholesterol in your diet is to limit foods high in saturated fats. Try to avoid:

Fatty meats

Full fat dairy products

Processed meats like salami and sausages

Snack foods like chips

Most takeaway foods, especially deep fried foods

Cakes, biscuits and pastries.

Diet tips to help reduce your cholesterol
The most important thing you can do to reduce your cholesterol level is to maintain a healthy lifestyle. You should try to:

Limit the amount of cholesterol-rich foods you eat.

Increase the amount and variety of fresh fruit, vegetables and wholegrain foods you have each day.

Control your blood sugar levels if you have diabetes. High blood sugars are linked to an increased risk of atherosclerosis.

Don’t cut out all dairy foods
Some people believe that cutting out dairy foods altogether is the safest option, but this isn’t true. Dairy foods are an important part of the daily diet and contribute many essential nutrients, especially calcium. You should switch to low fat types, which will reduce the risk from saturated fats.

You don’t need to avoid eggs and seafood
Some foods are high in cholesterol but they’re fine to eat in moderation, as long as your overall diet is low in saturated fats. For example:

Egg yolks – these are high in cholesterol but are rich in several other nutrients. It is recommended that you limit the number of eggs you eat to the equivalent of one a day (whole or in dishes).

Seafood – prawns and seafood contain some cholesterol but they are low in saturated fat and also contain healthy omega-3 fatty acids. Seafood is a healthy food and should not be avoided just because it contains cholesterol. However, avoid fried and battered seafood.

Foods that may lower cholesterol levels
Some studies have suggested that eating oats and legumes may lower LDL cholesterol. Food components like saponins (found in chickpeas, alfalfa sprouts and other foods) and sulphur compounds (like allicin – found in garlic and onions) may also have a positive effect on cholesterol levels.

Medication may be needed
For some people diet and lifestyle changes are not enough. High blood cholesterol levels are also linked to genetics. Some people inherit altered genes that cause high cholesterol, and this can usually not be changed by lifestyle or diet.

If you are at risk of coronary heart disease and your LDL cholesterol level doesn’t drop after scrupulous attention to diet, your doctor may recommend medications to force your LDL levels down. However, diet and exercise will still be important, even if you are taking medication. Your doctor may also refer you to a specialist who treats cardiovascular disease.

I know this is not about health as such but, i just went and did my tax and for the first time i have to pay the ATO, this is because Greater Southern health and BCS have not taken enough tax out durning the financial year. Apparently i’m not the first to be stung and stung hard.

Machado-Joseph disease (MJD)-also called spinocerebellar ataxia type 3-is a rare hereditary ataxia. (Ataxia is a general term meaning lack of muscle control.) The disease is characterized by clumsiness and weakness in the arms and legs, spasticity, a staggering lurching gait easily mistaken for drunkenness, difficulty with speech and swallowing, involuntary eye movements, double vision, and frequent urination. Some patients have dystonia (sustained muscle contractions that cause twisting of the body and limbs, repetitive movements, abnormal postures, and/or rigidity) or symptoms similar to those of Parkinson’s disease. Others have twitching of the face or tongue, or peculiar bulging eyes.

The severity of the disease is related to the age of onset, with earlier onset associated with a more severe form of the disease. Symptoms can begin any time between early adolescence and about 70 years of age. MJD is also a progressive disease, meaning that symptoms get worse with time. Life expectancy ranges from the mid-thirties for those with severe forms of MJD to a normal life expectancy for those with mild forms. For those who die early from the disease, the cause of death is often aspiration pneumonia.

The name, Machado-Joseph, comes from two families of Portuguese/Azorean descent who were among the first families described with the unique symptoms of the disease in the 1970s. The prevalence of the disease is still highest among people of Portuguese/Azorean descent. For immigrants of Portuguese ancestry in New England, the prevalence is around one in 4,000. The highest prevalence in the world, about one in 140, occurs on the small Azorean island of Flores. Recently, researchers have identified MJD in several family groups not of obvious Portuguese descent, including an African-American family from North Carolina, an Italian-American family, and several Japanese families. On a worldwide basis, MJD is the most prevalent autosomal dominant inherited form of ataxia, based on DNA studies.

The types of MJD are distinguished by the age of onset and range of symptoms. Type I is characterized by onset between 10 and 30 years of age, fast progression, and severe dystonia and rigidity. Type II MJD generally begins between the ages of 20 and 50 years, has an intermediate progression, and causes symptoms that include spasticity (continuous, uncontrollable muscle contractions), spastic gait, and exaggerated reflex responses. Type III MJD patients have an onset between 40 and 70 years of age, a relatively slow progression, and some muscle twitching, muscle atrophy, and unpleasant sensations such as numbness, tingling, cramps, and pain in the hands, feet, and limbs. Almost all MJD patients experience vision problems, including double vision (diplopia) or blurred vision, loss of ability to distinguish color and/or contrast, and inability to control eye movements. Some MJD patients also experience Parkinson’s-like symptoms, such as slowness of movement, rigidity or stiffness of the limbs and trunk, tremor or trembling in the hands, and impaired balance and coordination.

MJD is classified as a disorder of movement, specifically a spinocerebellar ataxia. In these disorders, degeneration of cells in an area of the brain called the hindbrain leads to deficits in movement. The hindbrain includes the cerebellum (a bundle of tissue about the size of an apricot located at the back of the head), the brainstem, and the upper part of the spinal cord. MJD is an inherited, autosomal dominant disease, meaning that if a child inherits one copy of the defective gene from either parent, the child will develop symptoms of the disease. People with a defective gene have a 50 percent chance of passing the mutation on to their children.

MJD belongs to a class of genetic disorders called triplet repeat diseases. The genetic mutation in triplet repeat diseases involves the extensive abnormal repetition of three letters of the DNA genetic code. In the case of MJD the code “CAG” is repeated within a gene located on chromosome 14q. The MJD gene produces a mutated protein called ataxin-3. This protein accumulates in affected cells and forms intranuclear inclusion bodies, which are insoluble spheres located in the nucleus of the cell. These spheres interfere with the normal operation of the nucleus and cause the cell to degenerate and die.

One trait of MJD and other triplet repeat diseases is a phenomenon called anticipation, in which the children of affected parents tend to develop symptoms of the disease much earlier in life, have a faster progression of the disease, and experience more severe symptoms. This is due to the tendency of the triplet repeat mutation to expand with the passing of genetic material to offspring. A longer expansion is associated with an earlier age of onset and a more severe form of the disease. It is impossible to predict precisely the course of the disease for an individual based solely on the repeat length.

Physicians diagnose MJD by recognizing the symptoms of the disease and by taking a family history. They ask detailed questions about family members who show, or showed, symptoms of the disease, the kinds of symptoms these relatives had, the ages of disease onset, and the progression and severity of symptoms. A definitive diagnosis of MJD can only be made with a genetic test. Unfortunately, many legal and ethical considerations, such as loss of health insurance and employment discrimination, may discourage some individuals with symptoms from getting tested. For the same reasons, many physicians recommend against genetic testing for those individuals who have a family history of the disease but do not show symptoms. For more information on genetic testing and counseling, please consult the organizations listed in the section titled “Where can I get more information?“

MJD is incurable, but some symptoms of the disease can be treated. For those patients who show parkinsonian features, levodopa therapy can help for many years. Treatment with antispasmodic drugs, such as baclofen, can help reduce spasticity. Botulinum toxin can also treat severe spasticity as well as some symptoms of dystonia. However, botulinum toxin should be used as a last resort due to the possibility of side effects, such as swallowing problems (dysphagia). Speech problems (dysarthria) and dysphagia can be treated with medication and speech therapy. Wearing prism glasses can reduce blurred or double vision, but eye surgery has only short-term benefits due to the progressive degeneration of eye muscles. Physiotherapy can help patients cope with disability associated with gait problems, and physical aids, such as walkers and wheelchairs, can assist the patient with everyday activities. Other problems, such as sleep disturbances, cramps, and urinary dysfunction, can be treated with medications and medical care.

The National Institute of Neurological Disorders and Stroke (NINDS) supports research on MJD and other neurodegenerative diseases in an effort to learn how to better treat, prevent, and even cure these diseases. Ongoing research includes efforts to better understand the genetic, molecular, and cellular mechanisms that underlie triplet repeat diseases. Other research areas include the development of novel therapies to treat the symptoms of MJD, efforts to identify diagnostic markers and to improve current diagnostic procedures for the disease, and population studies to identify affected families.

For more information on neurological disorders or research programs funded by the National Institute of Neurological Disorders and Stroke, contact the Institute’s Brain Resources and Information Network (BRAIN) at:

Abstract

Background

Progressive non-infectious anterior vertebral fusion is a unique spinal disorder with distinctive radiological features. Early radiographic findings consist of narrowing of the anterior aspect of the intervertebral disk with adjacent end plate erosions. There is a specific pattern of progression. The management needs a multi-disciplinary approach with major input from the orthopaedic surgeon.

Case report

We report a 12-year-old-female with progressive anterior vertebral fusion. This occurred at three vertebral levels. In the cervical spine there was progressive fusion of the lateral masses of the Axis with C3. Secondly, at the cervico-thoracic level, a severe, progressive, anterior thoracic vertebral fusion (C7-T5) and (T6-T7) resulted in the development of a thick anterior bony ridge and massive sclerosis and thirdly; progressive anterior fusion at L5-S1. Whereas at the level of the upper lumbar spines (L1) a split cord malformation was encountered. Situs inversus visceralis was an additional malformation. The role of the CT scan in detecting the details of the vertebral malformations was important. To our knowledge, neither this malformation complex and nor the role of the CT scan in evaluating these patients, have previously been described.

Conclusion

The constellations of the skeletal abnormalities in our patient do not resemble any previously reported conditions with progressive anterior vertebral fusion. We also emphasise the important role of computerized tomography in the investigation of these patients in order to improve our understanding of the underlying pathology, and to comprehend the various stages of the progressive fusion process. 3D-CT scan was performed to improve assessment of the spinal changes and to further evaluate the catastrophic complications if fracture of the ankylosed vertebrae does occur. We believe that prompt management cannot be accomplished, unless the nature of these bony malformations is clarified.

Background

Progressive non-infectious anterior vertebral fusion is a unique spinal disorder with distinctive radiological features. Early radiographic findings consist of narrowing of the anterior aspect of the intervertebral disk with adjacent end plate erosions. There is a specific pattern of progression. The management needs a multi-disciplinary approach with major input from the orthopaedic surgeon.

Case presentation

The child was referred to our department at the age of 12 years because of progressive thoraco-lumbar kyphoscoliosis and progressive limitations of neck movement (fig 1). She was born at full term, the product of an uneventful gestation. At birth her length, weight, and OFC were around the 10th percentile. The mother was a 27-year-old-healthy woman, gravida 1 abortus 0, married to a 32-year-old unrelated man.

At birth the parents observed a patch of hair over the lumbar region, and the child was investigated for this. A split cord malformation was identified, but the parents refused further interventions. At the age of 9 years the parents observed marked worsening of the spinal tilting and problems in bending over. Her head movements became difficult, particularly flexion, and this was accompanied by pain, more marked in the occipital and suboccipital regions. Walking a distance was difficult.

Her subsequent course of development has been described as within the normal limits, except for a moderate delay in motor development. There was no history of serious illnesses. Physical examination at the age of 12 years revealed; short stature. Her height was 121 cm (-3SD) and her head circumference was 53 cm (+2SD). She was of normal intelligence, and neurological examination, apart from a neuropathic bladder was unremarkable. Hearing and vision were normal. Stiffness of the neck was noted, with limitation of neck movement, particularly in flexion. Musculo-skeletal examination showed relative ligamentous hyperlaxity in the limbs, normal hands and feet, and the skeletal survey did not reveal limb abnormalities. The spinal column showed; severe, rigid, thoraco-lumbar kyphoscoliosis (fig 2, 3, 4, 5, 6).

Figure 2. Early stage of progressive vertebral fusion in which C4-C6, showed progressive anterior disc narrowing and end plate irregularities (arrows; a-b), whereas (arrow c) showed the development of a thick anterior and posterior bony ridge.

Figure 3. End stage of the progressive anterior vertebral fusion and the multi-level anterior fusion with disc space obliteration (T1-T5). There is a massive bony ridge extending anteriorly and in some vertebrae, posteriorly as well. However, (arrow b) note the sparing of the disc space posteriorly, whereas the anterior end plate is totally obliterated (arrow a). Absence of the normal concavity of the anterior body surface. There is a proliferation of sclerotic bone.

Figure 4. 3 d reconstruction CT scan showed the massive anterior fusion of (C7-T5) and (T6-T7), and the apparent anterior thick bony ridge (arrow), the latter developed secondary to progressive ossification of the anterior longitudinal ligament. from T7-T12; note the narrowing of the anterior part of the disc space, accompanied by erosion and irregularity of the anterior end plates.

Figure 5. Note sparing of the lumbar spines and progressive anterior fusion of L5-S1, and the exaggerated lumbar lordosis secondary to massive fusions of the thoracic vertebrae.

Figure 6. sagittal MRI imaging showed a split cord malformation, atthe level of L1, with a bony bar at the L1 level. It also revealed situs inversus visceralis. MRI imaging of the brain did not show any abnormality, and sagittal MRI of the cervical region did not reveal any Arnold-Chiari malformation. Other imaging studies such, as echo-cardio-Doppler was normal. The pelvic ultrasound showed normal ovaries, uterus and vagina, and renal ultrasound showed a normal genito-urinary system.

Laboratory tests included hematological indices, urine screening for metabolic abnormalities, karyotype (for the child and her parents) and rhematological screening. These were all normal and the HLA B-27 was negative.

Family history was unremarkable. Parents were reluctant to give any relevant information.

Progressive, non-infectious anterior vertebral fusion is a rare disorder; which is often referred to as the Copenhagen syndrome [1]. In the classical form, there may be a characteristic anterior defect in the affected vertebrae from shortly after birth, associated with narrowing of the anterior part of the disc space. This is accompanied by erosion and irregularity of the anterior end plates, and when the process of narrowing progresses with age, there is eventual disc space obliteration and bony ankylosis anteriorly, via a thick bony ridge [2].

It is important, to differentiate progressive non-infectious anterior vertebral fusion from the congenital form of block vertebrae, firstly by its clinical history and secondly, by using CT scanning (fig 3, 4, 5)

Scoliosis and kyphoscoliosis in children can occur either in isolation or as a part of a number of syndromes. Spinal malsegmenatation occurs in many of these syndromes, and this includes spondylocarpotarsal synostosis, spondylothoracic dysplasia, and other rare conditions [3,4]. All of these disorders have characteristic patterns of vertebral malformation, such as a posterior unsegmented spinal bar, congenital block vertebra, carpal and tarsal malformations [5].

Knutsson et al., [6] and others [1,2,7] reported children with progressive anterior vertebral fusion as the only malformation, and in none was this part of a syndrome.

Hughes et al., [8] reported three children with progressive fusion, and other congenital and developmental abnormalities. However, there were no distinctive clinical or radiological features signifying a syndromic association, apart from one child, who presented with spinal dysraphism, but neither cervical vertebral fusion nor situs inversus visceralis were described. Philip et al. [9] described involvement of both the upper thoracic (T2-T5) and lower thoracic (T10-S1) vertebrae, associated with radio-ulnar synostosis, exostosis, short and broad clavicles, and a balanced t(10;20)(p11;p13) translocation. There was no cervical vertebral fusion, spilt cord malformation or situs inversus visceralis.

Farrior et al., [10] described a male child with progressive vertebral fusion of the cervical, thoracic, and lumbar vertebrae, with additional manifestations, such as absence of one cervical vertebra, clefting of the vertebral bodies, and other few minor non-spinous abnormalities. The overall features were different from these found in our patient.

Fryns et al., [11], described a child who presented with progressive anterior vertebral body fusion, and other abnormalities such as a generalised overgrowth, especially of the hands and feet, and unusually thick skin and subcutaneous tissue of upper and lower limbs. There was facial dysmorphism. These features were not seen in our patient.

Tubbs et al., [12,13] reported split cord malformation in association with Klippel-Feil syndrome, and another child presented with split cord malformation and situs inversus totalis and scoliosis. They focused on the possibility that defects of the midline and laterality defects (situs inversus) are etiologically related. However, the reported patient manifested congenital blocked vertebrae and not the progressive condition as described here (fig 3, 4, 5, 6).

McRae and Barnum [14] reviewed 25 patients who presented with atlanto-occipital fusion. They found a bony continuity between the anterior arch of the atlas and the anterior lip of the foramen magnum. However, it is uncertain given the absence of sophisticated imaging techniques whether the bony continuity was because of progressive fusion, or was congenital. Situs inversus was not documented.

Kalifa et al., [15] described the nature of progressive non-infectious vertebral fusion, in which the lesions involved mainly the anterior end plates and sparing the posterior parts, whereas in congenital vertebral blocking (failure of segmentation) it usually involves the posterior part of the disk.

Conclusion

The constellations of the skeletal abnormalities in our patient do not resemble any previously reported conditions with progressive anterior vertebral fusion. We also emphasise the important role of computerized tomography in the investigation of these patients in order to improve our understanding of the underlying pathology, and to comprehend the various stages of the progressive fusion process. 3D-CT scan was performed to improve assessment of the spinal changes and to further evaluate the catastrophic complications if fracture of the ankylosed vertebrae does occur. We believe that prompt management cannot be accomplished, unless the nature of these bony malformations is clarified.

Competing interests

The author(s) declare that they have no competing interests.

Authors’ contributions

All authors contributed to this work and all read and approved the final manuscript.

A A: Was responsible for, writing the manuscript, Conception and design and data analysis.

F B C, and M B G: Data analysis.

F G and K K: Conception and design.

Acknowledgements

We wish to thank Dr. Michael Baraitser (Institute of Child Health-Clinical and Molecular Genetics-University College London) for his unlimited help. And we thank Dr. Marwa Hilmi, West Hertfordshire Hospitals, Watford Herts, UK, for her technical help.

We also thank the patient’s family for their cooperation and a written consent was obtained from the patient’s family for publication of study

Henoch-Schonlein purpura

Definition

Henoch-Schonlein purpura is a disease that involves purple spots on the skin, joint pain, gastrointestinal problems, and glomerulonephritis (a type of kidney disorder).

Alternative Names

Anaphylactoid purpura; Vascular purpura

Causes

Henoch-Schonlein is a type of hypersensitivity vasculitis and inflammatory response within the blood vessel. It is caused by an abnormal response of the immune system. It is unclear why this occurs.

The syndrome is usually seen in children, but it may affect people of any age. It is more common in boys than in girls. Many people with Henoch-Schonlein purpura had an upper respiratory illness in the previous weeks.

The purpose of this study was to describe the phenotypic characteristicsof an inherited myxomatous valvular dystrophy mapped to Xq28.

BACKGROUND

Myxomatous valve dystrophies are a frequent cause of valvulardiseases, the most common being idiopathic mitral valve prolapse.They form a group of heterogeneous diseases difficult to subclassify.The first mapping of the gene for a myxoid valvular dystrophyto Xq28 allowed investigation of the phenotype of affected membersin a large family and characterization of the disease.

X-linked myxomatous valvular disease is characterized by mitralvalve dystrophy frequently associated with degeneration of theaortic valves affecting males and, to a lower severity, females.The first localization of a gene for myxomatous valvular diseasesis the first step for the subclassification of these diseases.

Abbreviations and Acronyms

AML

= anterior mitral leaflet

F.VIII

= antihemophilic factor VIII

LAA

= left atrial area

LVOTD

= left ventricular outflow tract diameter

MVD

= myxomatous valve dystrophies

PML

= posterior mitral leaflet

RJA

= regurgitating jet area

Valvular disease with myxomatous degeneration forms a complexgroup of disorders. Common histological features and a clinicalcontinuum from isolated nonsyndromic valvular defects (e.g.,idiopathic mitral valve prolapse) to multivalvular diseasesand syndromic disorders (e.g., Marfan syndrome) make it difficultto subclassify these heterogeneous and complex pathologies.Defects in fibrillin (1) and collagen genes (2) have alreadybeen identified in syndromic valvular disease. In other valvulardystrophies with myxomatous degeneration, identification ofgenetic defects would appear to be an essential step in theirsubclassification.

In nonsyndromic valvular dystrophies with myxomatous degeneration,idiopathic mitral valve prolapse is by far the most common defect,occurring in 2% to 4% of the population (3) and displaying abroad clinical spectrum from mild valve defects without clinicalrepercussions to severe valvular disease (4). The valve anomalyis the main defect, but some studies are in favor of a morediffuse disease affecting other cardiac structures (5). Althoughthe exact prevalence of inherited cases is still uncertain,most familial forms appear to be inherited in an autosomal dominantmanner with incomplete penetrance (6). There is also clinicalevidence of genetic heterogeneity (7). Despite autosomal transmission,the disease is twice as frequent in females as in males (8),but more severe in the latter (9). A second type of inheritednonsyndromic valvular dystrophy was identified three decadesago by Monteleone and Fagan (10). This apparently rare disease,known as sex-linked valvular dysplasia, is supposedly transmittedas an X-linked recessive trait and may involve one or severalvalves in affected males. Both forms display classical histologicalabnormalities of myxomatous valve degeneration, with fragmentationof collagenous bundles within the valve fibrosa and accumulationof proteoglycan.

Because of the presence of valvular anomalies in type IV Ehlers-Danlossyndrome, it has been suggested that genes coding for collagenisoforms could be implicated in nonsyndromic valvular diseases.However, genetic studies have failed to find a link betweencollagen genes and familial mitral valve prolapse (11,12). Werecently identified a large French family with myxoid valvulardystrophy. Its cosegregation with mild hemophilia A enabledus to map the disease gene on Xq28 and characterize the geneticstatus of each patient (13).

The purpose of this study is to describe the clinical characteristicsof inherited X-linked valvular dystrophy. It shows that heterozygouswomen, in addition to obviously affected hemizygous men, canbe mildly affected by the disease. The fact that penetranceis complete in men and incomplete in heterozygous women (forwhom it increases with age) provides new insight into the clinicalcharacteristics of myxomatous valvular diseases and should improvegenetic analysis of inherited valvular diseases in general.

In our familial study, the proband was a 16-year-old boy withsevere aortic regurgitation as a result of valvular dystrophy.During his hospitalization for clinical evaluation before valvularsurgery, mild asymptomatic hemophilia A was detected. Subsequentinquiry revealed that a cousin had mitral valve regurgitationdue to valvular dystrophy and led to the identification of avery large five-generation family.

The study was conducted according to French guidelines for geneticresearch. Informed written consent was obtained from each familymember. Baseline measurement included a review of medical history,a physical examination with particular attention to the cardiovascularsystem and any connective tissues diseases, a 12-lead electrocardiogram,a two-dimensional echocardiography with color-coded Doppleranalysis, blood samples for genetic studies and quantificationof antihemophilic factor VIII. Ophthalmologic examination wasperformed in two affected members and was normal.

Echocardiography. The phenotypic assignment of family members was based on echocardiographicexamination.

Transthoracic M-mode and two-dimensional echocardiograms wererecorded according to the criteria of the American Society ofEchocardiography (14) using a Sonos 2000 (Hewlett-Packard Inc.,Andover, Massachusetts) with a 3.5-MHz probe, or a Sequoia C256(Acuson Inc., Mountain View, California) equipped with a multifrequencyprobe (3.5 to 2.0 MHz). Examinations were recorded on SVHS videotapesfor further analysis. All recordings were analyzed in a blindedmanner by two experienced physicians. Measurements of mitralvalves were performed on parasternal long-axis two-dimensionalimages (15). The length of each leaflet was determined justbefore valve closure. The thickness of the free edge of themitral leaflets was measured on a selected diastolic frame thatclearly separated the mitral leaflets and chordae. Valves wereconsidered dystrophic when the thickness was superior to 4 mm.Mitral annular diameter was calculated by measuring the lengthof the line between the anterior and the posterior leaflet hingepoints at end-diastole, just before the onset of the QRS complex,and at end-systole, before valve opening. Mitral valve prolapsewas considered to exist when two-dimensional recordings in theparasternal long-axis view showed protrusion of mitral leafletsinto the left atrium, crossing the line between the annularhinge points, and when the coaptation point of the leafletsremained at or above the mitral annular plane during systole(16). Mitral regurgitation was estimated quantitatively by transthoraciccolor Doppler flow mapping in three spatial planes. Dopplercolor gain was optimized by first turning down the setting completelyand then increasing the scale gradually until static backgroundnoise appeared (17). The severity of mitral regurgitation wasassessed by calculating the maximum regurgitating jet area (RJA)expressed as a percentage of left atrial area (RJA/LAA). Regurgitantflow signals localized in the vicinity of valve closure wereconsidered as physiological regurgitation, and these patientswere classified as unaffected (18). Mitral regurgitation wasrated as mild when RJA/LAA was <20%, moderate when 20% to<40%, and severe when 40% (19).

Measurements of left ventricular outflow tract diameter (LVOTD)were obtained from parasternal long-axis two-dimensional imagesat the level of aortic cusp insertion, and aortic root dimensionswere calculated from M-mode tracings. Aortic regurgitation wasconsidered to exist if an abnormal diastolic flow originatingfrom aortic cusps was identified in the left ventricular outflowtract. The diameter of the regurgitated jet (AJD) was measuredat its origin in the left outflow tract. The AJD/LVOTD ratiowas calculated for quantification of aortic regurgitation (20),which was rated as mild when <25%, moderate when 25% and<40% and severe when 40%. Tricuspid valve images were recordedin four-chamber apical views, and the pulmonary valve was analyzedin high left parasternal short-axis view.

Patients were defined as affected when echocardiographic examinationshowed mitral valve dystrophy associated or not with mitralvalve prolapse, aortic valve dystrophy or mild to severe aorticregurgitation.

Genetic study. A detailed linkage study of this family has been reported elsewhere(13).

Only male phenotypes were used to calculate the lod score becausethe number of affected males was sufficient to produce a highlysignificant score. Moreover, penetrance in obligate female carriers(Fig. 1), unlike that in males, was not complete and couldhave been misleading. Two-point linkage analysis found a maximallod score of 5.91 at = 0 for markers INT-13 and DXS1108. Basedon the results of the linkage study, patients who had valvulardefect and who inherited the complete haplotype were affected.Females heterozygous to this haplotype were defined as carriers.

Figure 1 Pedigree of the family. Black symbols denote males simultaneously affected by severe X-linked myxoid valvular dysplasia and hemophilia A, and hatched symbols indicate women showing abnormalities in echocardiography. Markers are not shown in order to simply the figure. Black bars represent the markers inherited from the ancestor who transmitted the disease. Marker order was as follows (top to bottom): DXS998, DXS8091, DXS8011, DXS8061, INT-13 and DXS1108. Blackened arrows indicate recombinations of parental alleles. A recombination event in male III-5 with a normal phenotype allowed us to delineate the linked area between marker DXS8011 and Xqter.

Statistical methods. Statistical analysis was performed using Student’s t testand the Mann-Whitney U test. A p value of less than 0.05 wasconsidered significant. Results are expressed as the mean ±SD.

The proband, a 16-year-old boy (Patient V-11), had class IIdyspnea according to the New York Heart Association classification.He was of normal size and morphology, and a physical examinationfound no connective tissue or joint abnormalities. Cardiac auscultationrevealed aortic regurgitant murmur, and echocardiography showedsevere aortic regurgitation. Aortic root dimensions were normalas confirmed by a nuclear magnetic resonance study of the thoracicaorta. The left ventricle was enlarged (end-diastolic diameter34 mm/m2), with normal systolic function. Mild hemophilia Awas diagnosed at the time of aortic valve replacement.

The same hematologic disease was identified in his cousin (PatientV-9) when he underwent valvuloplasty for severe mitral regurgitationdue to mitral valve dystrophy. This second case led to the identificationof a very large family.

Among the 318 members of the pedigree, 302 are still alive and89 accepted to participate in the study (Fig. 1): 43 females(36 ± 17 years) and 46 males (22 ± 15 years).A valve defect was found in 22 (9 males and 13 females) of thesesubjects. None of the subjects was the result of a consanguineousmating. No family member showed clinical evidence of syndromicdisorders such as Marfan or Elhers-Danlos disease.

Clinical characteristics of males. Among the 46 males (Table 1), 9 had obvious aortic and/or mitralvalve defect and were classified as affected, including 4 whounderwent valvular surgery. Subsequent to surgery, one patientwas asymptomatic and three had dyspnea (two class II, one classI). Seven of the nine affected males had mitral regurgitantmurmur. No differences were found between affected and unaffectedpatients concerning age and body surface area.

Figure 2 Parasternal long-axis two-dimensional view, at end diastole (A) and end systole (B), performed in an affected male (Patient IV-48), showing the structural abnormalities of the mitral valve with thickening of mitral valve leaflets (A) and a mild prolapse (B).

Aortic valve defect
As aortic valve dystrophy is difficult to assess by transthoracicechocardiography, we chose to quantify aortic regurgitation,which was associated with mitral valve dystrophy in six affectedmen. In three of these patients (III-6, III-16 and V-11), theseverity of aortic regurgitation led to valve replacement at42, 24 and 16 years of age, respectively. Histological examinationof the aortic valves found abnormalities similar to those describedin the proband. In the other three men (III-12, IV-50, and V-10),aortic regurgitation was quantified as mild or moderate, withan AJD/LVOTD of 0.1, 0.24 and 0.26, respectively. Aortic rootdiameters and the left ventricular outflows tract were normaland did not differ significantly in affected and unaffectedmen. The three remaining affected men had no detectable aorticvalve defect.

Affected males had larger left ventricular diastolic diameters,whereas left atrial diameters did not differ significantly.Ejection fractions were similar in the two groups.

Finally, the phenotypic status of men could easily be characterizedbecause affected patients had obvious valvular dystrophy clearlydifferentiating them from the normal phenotype.

Clinical characteristics of women. The linkage study was the key factor for detailed clinical analysisof X-linked valvular dystrophy, allowing identification of femalecarriers on the basis of their haplotypes and analysis of theexpression of the diseased gene in heterozygous women (Fig. 1).Among the 43 females in the pedigree, 17 who inherited theentire haplotype were heterozygous to the disease-associatedgene. Four other women (III-34, IV-41, V-1 and V-12) had inheritedpart of the haplotype, with recombination events within thecandidate region, so that their genetic status is unknown.

None of these women had obvious valvular dystrophy, and echocardiographicparameters such as leaflet thickness and mitral annulus, aorticroot, left ventricular outflow tract and the left ventriclediastolic diameters did not differ in heterozygous and unaffectedwomen (Table 2).

In two heterozygous women, the valvular defect could have beendue to another cause. Patient II-3, the 83-year-old mother oftwo affected males, had isolated moderate mitral regurgitationwithout valvular dystrophy or mitral valve prolapse and a historyof systemic hypertension. Patient IV-26, the 19-year-old daughterof an affected male, had an atypical valve defect with moderatepulmonary regurgitation without left valve defect.

According to echocardiographic data for genetically affectedwomen, the penetrance of the disease in heterozygous was estimatedas between 0.59 and 0.71, depending on the phenotypic statusof the last two cases. The penetrance of the disease-associatedgene in heterozygous women was age dependent, but valve defectswere seen in 5 out of 7 women over 40 years of age and in only5 out of 10 under 40.

Characteristics of women with undetermined genetic status. Echocardiographic examinations were normal in the four women(III-34, IV-41, V-1 and V-12) with recombination events in thecandidate area. The genetic status of Patient III-34 was considerednormal, as her son, who inherited the same haplotype, was unaffected.

Characteristics of women with normal genetic status. If it is assumed that Patient III-34 did not inherit the “diseased”haplotype, 23 women can be considered to have normal geneticstatus, including 3 (III-20, IV-1, IV-4) with a valve defectand 20 with normal echocardiography.

Patient III-20, a 64-year-old woman with isolated mild mitralregurgitation (RJA/LAA = 0.12) without valvular dystrophy ormitral valve prolapse, had received thoracic radiotherapy forbreast cancer 10 years before. Patient IV-1, with severe mitralregurgitation (RJA/LAA = 0.49), had experienced an episode ofprolonged fever, treated by antibiotics, shortly after delivery10 years before. A diagnosis of endocarditis was consideredbut never confirmed, despite the occurrence of mitral regurgitation.In these two cases, the valve defect could have been secondaryto radiotherapy or endocarditis. Patient IV-4, a 33-year-oldwoman with mild mitral regurgitation (RJA/LAA = 0.20) associatedwith moderate aortic regurgitation (AJD/LVOTD = 0.27), had noclinical history indicative of acquired valvular disease. Whenthese cases were taken into consideration, a risk of phenocopyof 0.12 was found for heterozygous women.

Valvular dystrophy with myxomatous degeneration is a frequentcause of valve defects. It has been well described in mitralvalve prolapse (21) and also occurs in aortic regurgitation(22,23). Although most affected patients are asymptomatic, theyrisk complications such as endocarditis, spontaneous cordalrupture and sudden death. Moreover, progressive worsening ofvalvular regurgitation can lead to heart failure. Within thelast decade, this disease has become an increasing cause ofvalvular surgery (representing almost 20% of such patients inour institution [unpublished data]).

The clinical spectrum of myxomatous valvular disorders, rangingfrom isolated mild defects to severe multivalvular lesions,is in favor of a heterogeneous disease that is in fact difficultto subclassify because of the absence of specific features,even at the histological level. To date, only genes for syndromicdiseases have been mapped or cloned (1–3), but the identificationof genetic defects would appear to be the key factor for determiningsubclassifications.

Isolated mitral dystrophy associated with billowing is the mostcommon form of myxomatous valvular disease. It is easy to diagnosean obviously affected patient but the continuum from normalto severely affected valves, and from isolated to multivalvulardefects, can complicate the identification of affected patients(5).

In our study, men were either clearly normal or affected; thelatter all had an obvious mitral valve dystrophy with thickerand longer leaflets and a mild prolapse similar to abnormalitiesdescribed in floppy mitral valve (21), associated with aorticregurgitation in two-thirds of cases. Valvular degenerationwas not associated with other detectable cardiovascular or morphologicaldefects. Clinical examinations of affected patients indicateda nonsyndromic disease because no features of a connective tissuedisease such as Marfan or Elher-Danlos syndrome were detected,nor were any signs of osteogenesis imperfecta. Moreover, thethoracic aorta, particularly the aortic root, was echocardiographicallyand histologically normal, and skin histology performed in oneaffected patient was normal.

An X-linked disease with anticipation. Several factors indicated that the inherited valvular diseasewas X-linked. There was no male-to-male transmission, the severityof myxomatous valvular disease was far greater in males andall affected men had mild hemophilia, whereas those with normalvalves showed normal F.VIII activity. This also suggested thatboth valvular dysplasia and hemophilia A were cosegregated inthe family and that the gene responsible for the valvular dysplasiawas closely linked to the factor VIII gene.

One of the most striking features of this disease is a tendencytoward earlier severity from generation to generation. Reconstructionof the haplotype of ancestors indicated that the male in generationI was probably genetically affected and responsible for thetransmission of the disease. Although no clinical cardiac analysisexists for this man, it is unlikely that he had severe valvulardisease because he died at 65 years of age from peritonitiswithout any indication of cardiovascular symptoms. In generationIII, three males were affected. The disease was identified whenthey were in their 40s, and two of them underwent valvular surgery,at ages 51 and 49 years. In generation IV, two men were affected.The diagnosis of valvular disease was made during their 20s,and at ages 30 and 24 years, they are still asymptomatic withmoderate mitral regurgitation. Finally, four males of generationV are affected by the disease. Two underwent valvular surgeryat the age of 17 years because of severe mitral (V-11) or aortic(V-9) valvular regurgitation, and two others (16 and 12 yearsold) are severely affected. This apparent tendency toward earlierseverity could actually be due to improvement of echocardiographictechniques. However, similar tendencies were noted in two previousdescriptions of this disease. In the family reported by Monteleoneand Fagan (10), a fourth-generation patient died of cardiacfailure due to valvular disease when he was eight months old,whereas several men from the previous generation were stillalive, although clinically affected. In the family describedby Newbury-Ecob et al (24), a fourth-generation baby died fromvalve defect and cardiac failure 24 h after birth, whereas hisgrandfather in the second generation was asymptomatic untilthe age of 25 years and underwent valve replacement at the ageof 41 years. This tendency toward earlier severity, called anticipation,needs to be confirmed in other families.

An X-linked disease with mildly affected female carriers. Our clinical observations differ from those previously describedfor X-linked valvular dysplasia, even though the same geneticdisease is probably involved. An important result not previouslydescribed is the identification of an intermediate phenotypein heterozygous women. With the mapping of the gene in monozygousmales, it has become possible to identify female carriers onthe basis of their haplotypes and to analyze the expressionof the disease gene. As has been demonstrated for idiopathicmitral valve prolapse, there was no clear delineation betweennormal and abnormal valves, and there is a continuum from normalto abnormal valves because some heterozygous women in our studyhad normal echocardiography, whereas others had mitral or aorticregurgitation, giving a penetrance value of 59% to 71%, whichincreased with age. Furthermore, valve defects were less severethan in men, as shown by the absence of differences in mitralvalve thickness, length and diameter between affected heterozygousand normal women and by a better outcome (no valvular surgery).This could have been due to the low accuracy of transthoracicechocardiography in identifying small valve defects.

Implications for genetics of myxomatous valve dystrophies. The clinical phenotype of patients with mitral valve prolapseconstitutes a continuum from Marfan syndrome to isolated mitralvalve prolapse. To emphasize the involvement of mitral valveprolapse, aorta, skeleton and skin, patients with connectivetissue disorder have been described using the acronym MASS phenotype(25). Isolated mitral valve prolapse is by far the most frequentsyndrome (4), and one study has identified at least two differentphenotypes with a strong family pattern (7). Both forms appearto be inherited in an autosomal dominant manner (6). This modeof inheritance was also identified in other studies that havereported family cases (26–28). However, epidemiologicalstudies have shown striking results that can hardly be explainedby this mode of inheritance. The mitral valve prolapse is twiceas frequent in females as in males (8), it is more severe inmen than in women (9), as confirmed by several surgical seriesof mitral valve prolapse as well as myxoid aortic valve regurgitationin which the patients were largely male (22,23), and no cleardelineation exists between normal and affected patients, especiallywomen. Although these results could have been due to hormonalas well as environmental factors, they are still surprisingfor an autosomal dominant disease.

Contrary to idiopathic mitral valve prolapse, X-linked valvulardystrophy seems to be a rare disease, described only twice (10,24).This could have been due to the rarity of the disease or tomisinterpretation in the mode of inheritance of the valvulardefect. Indeed, the presence of affected heterozygous women,particularly in small pedigree, the tendency toward earlierseverity (the anticipation of the disease), the risk of phenocopiesand the low sensitivity of echocardiography could be clinicallymisleading. Owing to the presence of these confusing factors,it is possible that some patients with myxomatous valve defectsmay have been affected by an unidentified X-linked valvulardisease. In this respect, only male-to-male transmission canrule out an X-linked disease.

Conclusions. It is quite likely that myxomatous valvular diseases are heterogeneousand that myxoid degeneration is the final pathway for severalprotein defects that will not be identified with conventionalclinical tools. The first localization of a gene for nonsyndromicmyxomatous valvular diseases should facilitate the subclassificationof this complex group of diseases. Ultimately, the cloning ofthe gene will give a new insight into the pathophysiology ofthese diseases.

Abstract

A case is reported of a 30-year-old male patient, who presented a purulent area in his scalp, which was initially diagnosed as Celsus kerion. The microbiologic examinations were negative for fungi and isolated only Staphylococcus aureus. The lesion was controlled with systemic antibiotics, which enabled the visualization of tufted hairs inside a cicatricial alopecia. There were two recurrences that were again controlled with systemic antibiotics. Surgical excision was indicated.

Keywords: Folliculitis; Staphylococcus aureus

INTRODUCTION

Folliculitis decalvans constitutes a subgroup of cicatricial alopecia, in which a bacterial component plays an important role in the follicular destruction, thereby differing from pseudopelade of Brocq, discoid lupus and pilar lichen planes, in which the alopecia occurs without infection.

The classic clinical picture of folliculitis decalvans, as described by Quinquaud in 1888,1 is characterized by follicular pustules associated to central cicatricial areas withoat hair2 secondary to the bacterial aggression and/or inflammation. Clinical pictures with intense suppuration and formation of intercommunicating abcessos constitute another variant denominated dissecting follicerlitis of the scalp.2

In 1978, another clinical picture was described bv Smith and Sanderson, in which the follicles present in tufts,3 as a result of a particular cicatritiation after the inf annnatorv process. There are approximately 30 cases published, though none in the Latin-American literature.

CASE REPORT

Male patient, 30 years old, presented with a lesion in the scalp that had appeared ttivo months previously.

At der matological exam, plaque was observed with fes­tering crusts measuring five centimeters in diameter located in the vertex. With diagnostic hyotheses of Infectious folliculitis and Celsus kerion, bacteriological exams were requested, which isolated Staphylococcus aureus. Mycological exams were also performed and the result was negative.

The patient was treated with oral cephalosporin and four consecutive doses of I50mg fluconazole every five days, in view of the possibility that the milcological exam was false-negative, a significant improvement was observed. Following the falling off the crust and decrease in the suppuration it was possible to observe areas of alopecia, follicular pustules and presence of tufted hair (Figure 1).

Four weeks later there was a recurrence and further microbiological exams requested, with identical results to the first. The lesions were controlled with oral lymecycline. After nvo months there was a third recurrence, again con­trolled with oral lymecycline and surgical exeresis of the affected area was indicated.

Between recurrences several topical antibiotics were maintained, such as neomycin, erythromycin, clindamycin, nurpirocin and rifarnpicin, without a satisfactory response.

DISCUSSION

Tufted folliculitis decalvans (TFD) is considered a variant of the classical folliculitis decalvans4 and both have in common areas of cicatricial alopecia and follicular- pustules, the important difference being the tufts of remaining hair.

Normally only one area is affected, with few reports of multiple lesions.4 The ratio of male and female patients is 3:1 and in general it involves individuals in their third or fourth decade of life.

Pathogenically it is an accepted fact that the process triggered by the infection provokes a fibrosis of the superior third of the perifollicular dermis, leading to a confluence of the remaining follicles,4,5 which has been confirmed histologically by several authors, since the inflammatom infiltrate is limited to the papillary and media dermis, non affecting the reticular dermis and hypodermis.6 In the classic folliculi­tis decalvans a destruction of the follicles occurs with fibrosis of the entire dermis.5

Pili multigemini appear not to precede thelesions of TFD, as the patients refer normal scalp before onset of the picture. Furthermore, histologically in TFD there is a convergence of the follicles and not a true coalition, as in pili multigemini.6 In that the former presents an external radicular sheath in common, while only the internal one is individualized.7 It has been reported that a patient initially presented only follicular pustules and after three years tufts were observed,8 thereby demonstrating their appearance subsequent to the bacterial process.

It is interesting that there are nvo reports of TFD in patients with pernhigus vulgaris,9,10 and it has been sugges­ted that the erosions provoked by the pemphigus facilitated an infection by S. aureus.

Another two reports refer to the presence of tufts in folliculitis keloidalis of the neck11,12 In this situation an important fibrosis also occurs, characteristic of the keloids, leading to the formation of the tufts. Both these entities can be easily differentiated clinically by the presence of keloids.1

The bacteriological exam almost always isolates S. aureus,1,4,6,8,13 and on rare occasions an association with other bacteria, such as Klebsiella or Providencia;14 there have been no reports of the isolated detection of a bacteriron other than Staphylococcus.

Treatment should be initiated with systemic antibio­tics and based on an antibiograin, which enables some cases to be controlled. However recinrence or resistance have been described by several authors,1,4,6,11 causing the disease to become chronic as ire the current case report, in such situations exegesis of the area is indicated.1,6 Techniques using laser depilation can offer an alternative in resistant cases, thereby avoiding a surgical management.